Significance

Signaling pathways form complex networks of biochemical reactions, but inferring the topology of such networks and measuring how they are remodeled in disease is still challenging. Using MS, our study defined the circuitry and plasticity of a kinase signaling network de novo, with unprecedented depth and without prior assumptions of its topology. In addition, we observed a degree of stochasticity in how the network was remodeled upon chronic inhibition of phosphoinositide 3-kinase (PI3K) or mammalian target of rapamycin complexes 1/2 (mTORC1/2), suggesting that the initial condition of the system was not the only determinant of how cells become resistant to targeted therapies. These observations may have implications for our ability to predict the evolution of signaling networks during therapy to prevent the acquisition of resistance.

Abstract

Our understanding of physiology and disease is hampered by the difficulty of measuring the circuitry and plasticity of signaling networks that regulate cell biology, and how these relate to phenotypes. Here, using mass spectrometry-based phosphoproteomics, we systematically characterized the topology of a network comprising the PI3K/Akt/mTOR and MEK/ERK signaling axes and confirmed its biological relevance by assessing its dynamics upon EGF and IGF1 stimulation. Measuring the activity of this network in models of acquired drug resistance revealed that cells chronically treated with PI3K or mTORC1/2 inhibitors differed in the way their networks were remodeled. Unexpectedly, we also observed a degree of heterogeneity in the network state between cells resistant to the same inhibitor, indicating that even identical and carefully controlled experimental conditions can give rise to the evolution of distinct kinase network statuses. These data suggest that the initial conditions of the system do not necessarily determine the mechanism by which cancer cells become resistant to PI3K/mTOR targeted therapies. The patterns of signaling network activity observed in the resistant cells mirrored the patterns of response to several drug combination treatments, suggesting that the activity of the defined signaling network truly reflected the evolved phenotypic diversity.

Topology could help better connect the people and places in these chaotic communities. But some who’ve studied slums and their multifaceted origins fear that applying such mathematical approaches won’t help, and could even make the problem worse.

A study estimates 107,000 cases of premature death in the United States due to anthropogenic particulate matter PM2.5 in 2011, with a societal cost of $886 billion, highlighting the importance of modeling emissions at fine spatial scales to prioritize emissions mitigation efforts.

A study suggests a potential treatment approach for severe peanut allergies; treatment inhibited more than 80% of the allergic response to crude peanut extract in serum from 14 of 16 patients and reduced basophil activation in whole blood from three patients.

A study quantifies the drivers of public interest in more than 600 bird species in the United States by comparing summaries of online searches for each species to the species’ abundance and spatial distribution.